PROJECT SUMMARY/ABSTRACT Metabolic syndrome (MetS) is a rising public health threat now affecting a quarter of the world adult population and a third of the US adult population. The implications of this health condition are significant: those afflicted with MetS are twice as likely to die from and three times as likely to develop coronary heart disease or stroke, compared to those without it. People with MetS are also at a five times greater risk of developing Type 2 diabetes. As a result of its global burden, substantial effort has been made to identify risk factors for both diabetes and MetS in attempts to target prevention and early intervention. Inorganic arsenic exposure has been associated with numerous health outcomes, including cancer, cardiovascular disease, diabetes, and MetS. Evidence suggests that methylation of inorganic arsenic to dimethylated arsenic (DMA) facilitates its excretion and detoxification; this is supported by findings that higher %DMA has been associated with lower arsenic-related health effects, particularly cancer and cardiovascular disease. Arsenic metabolism profiles, however, present differently for metabolic-related outcomes, with lower %DMA being associated with diabetes, BMI and MetS, including in prospective studies. One-carbon metabolism (OCM), an essential biochemical cycle dependent on B-vitamins and other nutrients such as choline, appears to play a role in both arsenic metabolism and metabolic outcomes. Little is known, however, on the interplay between OCM and arsenic metabolism for MetS development, especially in US populations. In our proposed research, we aim to fill in these important gaps in research using existing data from the Strong Heart Family Study, a prospective family- based cohort developed to investigate genetic and non-genetic factors for cardiovascular disease, diabetes, and their risk factors in American Indians. First, we plan to evaluate the association of arsenic exposure and arsenic metabolism with incident MetS in this population. Second, we will separately evaluate the associations between intake of OCM vitamins (choline, folate (B9) and vitamins B12, B6, and B2) with arsenic metabolism as well as with incident MetS. We will then assess the influence of OCM in the relationship between arsenic exposure and metabolism with MetS by evaluating the change in the magnitude and significance of the association between arsenic metabolism and MetS after accounting for measures of OCM. Lastly, we will attempt to better characterize mechanistic pathways in the diabetogenic effects of arsenic exposure and metabolism through metabolomic data. Improved understanding of modifiable risk factors for MetS, such as arsenic exposure and nutrient-regulated OCM, are essential to identifying high risk populations and developing early preventative interventions